In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 5_Supplement ( 2016-03-01), p. PR07-PR07
Abstract:
Introduction: Integrated clinical sequencing (RNA and whole-exome) has been used to assist in clinical decision making for pediatric and young adult cancer patients in the Peds-MiOncoSeq study. Here we present novel biological findings from this study that shed light onto disease pathogenesis. Actionable sequencing results affecting patient management have been presented previously by our group. Experimental Procedures: Peds-MiOncoSeq is an observational, consecutive case series (May 2012-October 2014) of 102 pediatric and young adult cancer patients (ages 0-22 years) at the University of Michigan who underwent exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing with genetic counseling. Sequencing was performed with standard protocols on an Illumina HiSeq 2000 or 2500. Sequence reads were aligned to the reference genome build hg19, GRCh37. Somatic and germline variant calling was performed with VarScan2 and Pindel for indels; gene fusion identification with Tophat2; and gene expression with Cufflinks. Recommendations were discussed in a Precision Medicine Tumor Board and reported to treating physicians and families. Results: In 91/102 patients (28 hematologic and 63 solid tumor patients), there was adequate tumor tissue for sequencing and analysis. Of these, 42 had potentially actionable molecular events (previously presented by our group), while another 44 patients yielded informative but non-actionable biology only. We uncovered both known and novel disease-associated mutations. In particular, sarcomas had frequent TP53 mutations (8/23 patients), FGF pathway activation (5/23), and PDGF pathway activation (3/23). Other recurrently mutated genes included beta-catenin in liver tumors (3/6), FLT3 in leukemias (3/20), and ATRX in neuroblastoma (3/7). Across disparate tumor types, we observed MAPK pathway activation (via NF1 loss (n=3), or RAS (n=5) or RAF mutations (n=3)), SWI/SNF complex inactivation (n=9), NOTCH1/2 aberrations (n=7), and STAG2 mutations (n=3). Surprisingly, we discovered mutations in the transcription factor HNF1A in both leukemia and osteosarcoma, which is not known in these cancers. 12 patients had significant germline variants including unexpected rare cancer risk genes (BAP1 in melanoma, BARD1 in neuroblastoma) which revealed potential cancer predisposition syndromes for several patients. Interestingly, an activating germline MITF E318K mutation was discovered in an omental mass of unclear etiology with hematolymphoid histology. Most notably, 32/91 patients had a driving gene fusion. Fusions were more common in hematologic compared to solid tumors (OR=4.0, 95% CI 1.6–10.4). However, sarcomas displayed a comparable rate to hematologic malignancies: 52% of sarcomas, 59% of liquid tumors, 12% of other solid tumors had a driving fusion. Sarcomas also harbored actionable kinase fusions such as LMNA-NTRK1 and ATIC-ALK. Recurrent BCOR-CCNB3 fusions were further found in sarcoma and in a spindle cell carcinoma, which is previously unknown in this tumor type. Other novel findings were a previously unknown YAP-MAML2 fusion in meningioma, a LRP6-ETV6 fusion in glioma, a EBF1-PDGFRB fusion in leukemia, and lastly a SFPQ-TFE3 fusion in a colon adenocarcinoma, which is the first description of this fusion in this tumor type. Conclusions: Here, we catalog the landscape of tumor biology in the Peds-MiOncoSeq study. Highlighted in our study are somatic HNF1A mutations and rare germline variants (MITF, BAP1, BARD1). Most importantly, our study demonstrates the importance of gene fusions across cancer subtypes, and we describe many novel fusions warranting further study. Our work therefore provides a framework for clinical sequencing programs as well as a rich collection of novel disease-associated molecular events. This abstract is also presented as Poster A44. Citation Format: John R. Prensner, Rajen J. Mody, Yi-Mi Wu, Robert J. Lonigro, Xuhong Cao, Sameek Roychowdhury, Pankaj Vats, Kevin M. Frank, Irfan Asangani, Nallasivam Palanisamy, Raja M. Rabah, Laxmi Priya Kunju, Jessica Everett, Elena M. Stoffel, Jeffrey W. Innis, Dan R. Robinson, Arul M. Chinnaiyan. The landscape of molecular aberrations in pediatric and young adult cancer patients undergoing clinical sequencing for disease management: Novel biological findings from the Peds-MiOncoSeq study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr PR07.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.PEDCA15-PR07
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
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2036785-5
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1432-1
detail.hit.zdb_id:
410466-3
